The primary objective of this study is to investigate the role of glyoxylic acid in normal and disease conditions. The disease conditions include: dietary thiamine deficiency (beriberi in human beings), Wernicke's encephalopathy (usually associated with chronic alcoholism), and the fetal genetic disease subacute necrotizing encephalomyelopathy (Leigh's disease). All of these disorders are associated with defective thiamine function. The experimental animals will be: (1) thiamine-deficient rats and (2) kittens with the inherited feline tremor disorder, which appears to be an excellent animal model for Leigh's disease. Markedly elevated glyoxylate levels in tissues, serum and urine have been reported for thiamine-deficient animals; an increase in urinary glyoxylate has been reported for Leigh's disease. Since glyoxylate is a known toxin, studies will be directed toward elucidation of: (1) factors that increase glyoxylate levels and (2) the molecular basis of glyoxylate action. The enzyme activity alpha-ketoglutarate:glyoxylate carboligase requires thiamine pyrophosphate as cofactor and utilizes glyoxylate as substrate. Because of the relationship between thiamine and glyoxylate, the role of this enzyme in metabolism will be investigated. Glycine is a putative neurotransmitter; the highest levels of glycine are found in areas of the CNS where major pathologic changes occur in thiamine deficiency and in Leigh's disease. Since glyoxylate is an immediate precursor of glycine, the effect of glyoxylate on glycine levels and function will be investigated. As part of these studies, the penetration of glyoxylate across the blood-brain barrier in normal and thiamine-deficient animals will be measured. The metabolic effects of acute and subacute toxic doses of glyoxylate in rats will be compared in order to elucidate the effect of glyoxylate in thiamine deficiency.